Therapy of leukemia is usually aimed at selective destruction of all malignant cells, permitting regrowth of surviving normal hematopoietic cells. Two acute lymphoblastic leukemic patients treated with whole body irradiation and bone marrow transplantation, relapsed with cytogenetic evidence of leukemia in donor cells. This strongly suggests a viral etiology for at least this form of human leukemia, and requires that the approach to treatment be rethought and adjusted to include not only abolishment of all existing malignant cells, but also prevention or minimization of subsequent transformation of normal cells. The purpose of the present study is to develop a model with which the mechanisms involved in leukemic transformation in vivo can be delineated. Transplantation of normal isogeneic and H-2 compatible allogeneic bone marrow cells into lethally irradiated leukemic mice and cytogenetic identification of leukemic cells in relapse, should enable us to separate host and donor cell related factors influencing transformation. The AKR strain of mouse has a very high incidence of spontaneous lymphatic (thymic) leukemia. Isogeneic AKR/TI Ald mice and H-2k histocompatible allogeneic CBA mice are available with cytogenetic markers. After lethal irradiation of leukemic AKR mice and injection of sufficient numbers of normal hematopoietic cells of a different cytogenetic type to prevent death due to hematopoietic depletion, frequency, latency and cytogenetic type of cells in leukemic relapse will be determined. Preliminary experiments have shown that leukemic relapse and transformation of AKR donor cells can occur in this system. Experiments are described which are designed to determine whether the factors important in transformation are inherent in the donor cells and activated by transplantation or are related to the host or both.